Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology with mortality still approaching 10% in 5 years. The leading cause of death in SLE are infections due to the toxicity of immunosuppressant medications. Therefore, a significant unmet need exists for effective and non-toxic medications to treat SLE. Our central hypothesis has been formulated on the basis that effective treatment should target key checkpoints of pathogenesis, such as the depletion of reduced glutathione (GSH), which underlies the activation of the mechanistic target of rapamycin (mTOR) and inflammatory lineage specification of T cells, B-cell activation and antinuclear autoantibody production in SLE. The rationale for this study is supported by evidence that 1) GSH is depleted in peripheral blood lymphocytes (PBL) of SLE patients; 2) GSH depletion contributes to mTOR activation that drives T-cell dysfunction in SLE; 3) administration of N- acetylcysteine (NAC), which serves as a cell-permeable amino acid precursor of GSH, blocks the development of murine lupus; and 4) the preliminary studies suggest that NAC is safe, reverses GSH depletion and mTOR activation and improves disease activity in SLE patients. In our completed double-blind placebo-controlled pilot study, NAC was tolerated by 100% of patients on 1.2 g/day and 2.4 g/day dosages, while 33% of those receiving 4.8 g/day had reversible nausea. Placebo and 1.2 g/day NAC did not influence disease activity. Although both 2.4 g/day and 4.8 g/day NAC dosages showed preliminary evidence for clinical efficacy, 4.8 g/day NAC achieved greater drops in SLEDAI and BILAG scores. NAC raised GSH, blocked mTOR, and expanded T regs. The proposed phase II trial will employ the SLE Responder Index (SRI), as a clinically meaningful primary outcome measure that provides easily interpretable results and yields a feasible sample size that is associated with adequate power to detect therapeutic benefit over 1 year. To minimize potential intolerance of NAC and subject withdrawal, the study design includes an open-label dosage titration period. Patients who tolerate 2.4-4.8 g daily NAC for 3 months will be randomly assigned 1:1 to continue treatment on their tolerated dosage of NAC or matching placebo for 9 additional months. Beyond the premise of validating clinical efficacy and durability of this therapy in SLE, the proposed studies will test the hypothesis that depletion of GSH and cysteine and activation of mTOR predict immunobiological and clinical responsiveness to NAC. The proposed studies will significantly advance our understanding of immune-metabolic pathways that control T-cell lineage specification with translational relevance for the pathogenesis and treatment of lupus. The approach is innovative as it will employ a safe therapeutic intervention to define the role of cysteine depletion in redox-dependent mTOR activation and pro-inflammatory T-cell development in lupus patients in vivo. The results will bring new perspectives to our understanding of disease pathogenesis with broad translational relevance for clinical management of patients with SLE.